In this episode, the human body has a skin abrasion which creates a hole sucking cells out of the body. Bacteria also invade the human body through the hole, so the white blood cells have to work tirelessly to stop them spreading further. Platelets eventually arrive to lay a fibrin mesh that covers the hole. This stops further entry of bacteria and allows white blood cells to eliminate the remaining bacteria. At the end of the episode, red and white blood cells become stuck in the blood clot as it is carted off by platelets.

How would the events of this episode work in real life? Join us as we dive into why the skin is important and how the damaged skin is repaired.

Skin and its multiple functions

The skin is the largest organ in the human body, covering the external surface and possessing multiple functions. It provides a protective barrier against heat, cold, light and moisture from the external environment while preventing pathogens from entering the human body. The skin also senses variables such as temperature and pain so that the body can respond to external stimuli and also stores water and fat.

The skin has three layers:

• Epidermis: the epidermis presents a tough, continuously renewing barrier against the external environment that is provided by keratin in keratinocytes. These cells divide from the base membrane and move upwards as they mature before they are shed. The epidermis also contains melanocytes that produce melanin, the chemical that protects skin against UV rays and contributes to your skin colour.
• Dermis: the dermis is the thickest and most feature-laden layer of the skin. Capillaries in the dermis supply cells in the epidermis with oxygen and nutrients and carry off carbon dioxide, wastes and heat. Collagen in the dermis also provide strength and flexibility to the skin.
• Hypodermis: also known as subcutaneous tissue, this layer contains a network of fat tissue and collagen. Fat tissue acts to store energy but it can also be used as an insulator and a shock absorber. Blood and lymph vessels and nerves also cross over the hypodermis.

Did you know? Keratinocytes within the skin can naturally synthesise vitamin D. UVB rays catalyse the conversion of 7-dehydrocholesterol precursor to previtamin D which spontaneously changes shape to become vitamin D.

A skin abrasion is a wound that is produced when the skin scrapes against a rough surface such as a footpath or road. Here, the skin is broken which allow pathogens to enter the body to start an infection. Your body responds to this by initiating a process called inflammation. By releasing signalling proteins such as histamine and cytokines, the blood vessels dilate and become more permeable which allow more white blood cells to access the abrasion. White blood cells engulf and degrade pathogens, preventing them from spreading further in the body while the wound is being healed. Blood vessels are also broken in a skin abrasion, resulting in bleeding where blood leaks out from the abrasion. This initiates a process called haemostasis.

Describing haemostasis

In an intact blood vessel, blood is kept fluid, unable to spontaneously form clots. However, when blood vessels are broken during a skin abrasion, blood transforms from a liquid to a gel via a process called coagulation. This is mediated by haemostasis which is designed to seal the broken blood vessel to stop bleeding. Haemostasis is split into two stages: primary haemostasis where a platelet plug is established and secondary haemostasis where the resultant blood clot is stabilised by the fibrin mesh. Both of these stages occur simultaneously.

Before haemostasis can start; however, blood flow to the wound has to be reduced. This is mediated by vasoconstriction, where blood vessels squeeze inwards as smooth muscle cells in the blood vessel wall contract. This reduces blood flow which not only enables formation of a stable blood clot but also minimises bleeding and blood loss.

Primary haemostasis

Primary haemostasis is the process of forming a platelet plug onto the damaged blood vessel. Initially, receptors on platelets bind to factors that enable platelet activation and adhesion onto the blood vessel wall. This is primarily mediated by the GP1b-IX-V complex and GPVI binding to von Willebrand Factor (vWF) and collagen on the blood vessel wall respectively. Platelet activation also leads to conformational changes on integrins which bind to multiple ligands to reinforce inter-platelet adhesion. For instance, integrin α_IIbβ₃ binds to multiple ligands such as fibrinogen and vWF to mediate platelet aggregation. Activated platelets also release additional factors such as ADP and thromboxane A₂ from their granules to activate nearby platelets. This enables further platelet aggregation which expands the platelet plug.

Secondary haemostasis

Secondary haemostasis is the formation and deposition of a fibrin mesh onto the platelet plug which strengthens and stabilises the blood clot.

In the episode, the Platelets carry the fibrin around the blood vessel (they even wash it in the river!). When it came time to seal the hole, they attached the fibrin onto the coagulation factors before throwing it over the hole. In reality, fibrin does not normally circulate in the bloodstream but it is present in its soluble form fibrinogen. It is converted to fibrin by the enzyme thrombin which in turn is activated by the coagulation cascade. This cascade is made up of a series of enzymes and cofactors collectively named coagulation factors. There are three parts to the coagulation cascade:

• Extrinsic pathway (orange): tissue factor is a cofactor of factor VIIa that is normally sequestered to the outside surface of the blood vessel. However, when the blood vessel is damaged, tissue factor is exposed to the bloodstream which combines with factor VIIa. This initiates a cascade of coagulation factors which lead to inactive prothrombin being converted to active thrombin.
• Common pathway (blue): active thrombin cleaves fibrinogen, a soluble plasma protein, to fibrin, an insoluble protein. Fibrin threads are joined together by factor XIIIa to form a fibrin mesh that wraps around the platelet plug, not only stabilising the platelet plug but also forming a blood clot holding platelets, blood cells and other substances together while the wound is being healed.
• Intrinsic pathway (green): something not described in the anime, but thrombin also promotes a positive feedback loop to coagulation by cleaving coagulation factors to initiate another coagulation cascade as well as PAR1 and PAR4 to activate platelets.

What happens after haemostasis?

After haemostasis stops further bleeding and pathogen invasion, the skin abrasion heals itself. Initially, the clot reduces in size by platelets shrinking and the fibrin mesh contracting via further fibrin cross-linking. This brings the vessel walls together so that the damage can be repaired. Following clot contraction, fibrinolysis breaks down the blood clot due to plasmin, an enzyme, breaking down fibrin into small pieces.

Following the disappearance of the blood clot, the skin abrasion heals itself with new tissue during the proliferative stage. The skin abrasion is pulled together by myofibroblasts while new blood vessels are grown to transport oxygen and nutrients to the healing wound. This allows new tissue, collagen and extracellular matrix to be generated and deposited in the skin abrasion before epithelial cells are grown over it. Finally, during the maturation phase, collagen fibres are reorganised and cross-linked to close the skin abrasion while cells that are no longer needed are removed via apoptosis.

Did you know? A scab is a hard layer that covers the wound as the blood clot dries out. This prevents pathogens from entering the wound while the tissue heals. Pus may also emerge from the wound. Pus is a thick fluid that consists of dead pathogens, tissues and white blood cells (specifically neutrophils).

Conclusion

The skin is a very important organ with multiple important functions. It acts as a barrier against the changing external environment, particularly pathogens that want to cause an infection. Should the skin be breached such as a skin abrasion, inflammation attracts white blood cells to the wound in order to restrict pathogen spread inside the human body. Meanwhile, haemostasis stops further bleeding via formation and stabilisation of a blood clot. The blood clot is later dissolved as the wound repairs itself to generate a repaired skin barrier against the external environment.

Tune into the next blog post where I explain influenza and how T cells are activated in the body. See you then!